Spatial Extent of Amyloid-β Levels and Associations With Tau-PET and Cognition
Authors: Hazal Ozlen, Alexa Pichet Binette, Theresa Köbe, Pierre-François Meyer, Julie Gonneaud, Frédéric St-Onge, Karine Provost, Jean-Paul Soucy, Pedro Rosa-Neto, John Breitner, Judes Poirier, Sylvia Villeneuve, Angela Tam, Anne Labonte, Alexa Pichet Binette, Anne-Marie Faubert, Axel Mathieu, Cecile Madjar, Charles Edouard Carrier, Christian Dansereau, Christina Kazazian, Claude Lepage, Cynthia Picard, David Maillet, Diane Michaud, Doris Couture, Doris Dea, Claudio Cuello, Alan Barkun, Alan Evans, Blandine Courcot, Christine Tardif, Clement Debacker, Clifford Jack, David Fontaine, David Knopman, Gerhard Multhaup, Jamie Near, Jeannie-Marie Leoutsakos, Jean-Robert Maltais, Jason Brandt, Jens Pruessner, John Morris, John Breitner, Judes Poirier, Laksanun Cheewakriengkrai, Lisa-Marie MÃ¼nter, Louis Collins, Mallar Chakravarty, Mark Sager, Marina Dauar-Tedeschi, Mark Eisenberg, Natasha Rajah, Paul Aisen, Paule-Joanne Toussaint, Pedro Rosa-Neto, Pierre Bellec, Penelope Kostopoulos, Pierre Etienne, Pierre Tariot, Pierre Orban, Reisa Sperling, Rick Hoge, Ronald Thomas, Serge Gauthier, Suzanne Craft, Sylvia Villeneuve, Thomas Montine, Vasavan Nair, Veronique Bohbot, Vinod Venugopalan, Vladimir Fonov, Yasser Ituria-Medina, Zaven Khachaturian, Eduard Teigner, Elena Anthal, Elsa Yu, Fabiola Ferdinand, Galina Pogossova, Ginette Mayrand, Guerda Duclair, Guylaine Gagne, Holly Newbold-Fox, Illana Leppert, Isabelle Vallee, Jacob Vogel, Jennifer Tremblay-Mercier, Joanne Frenette, Josee Frappier, Justin Kat, Justin Miron, Karen Wan, Laura Mahar, Leopoldina Carmo, Louise Theroux, Mahsa Dadar, Marianne Dufour, Marie-Elyse Lafaille-Magnan, Melissa Appleby, Melissa Savard, Miranda Tuwaig, Mirela Petkova, Pierre Rioux, Pierre-FranÃ§ois Meyer, Rana El-Khoury, Renee Gordon, Renuka Giles, Samir Das, Seqian Wang, Shirin Tabrizi, Sulantha Mathotaarachchi, Sylvie Dubuc, Tanya Lee, Thomas Beaudry, Valerie Gervais, Veronique Page, Julie Gonneaud, GÃ¼lebru Ayranci, Tharick Pascoal, Rene Desautels, Fatiha Benbouhoud, Eunice Farah Saint-Fort, Sander Verfaillie, Sarah Farzin, Alyssa Salaciak, Stephanie Tullo, Etienne Vachon-Presseau, Leslie-Ann Daoust, Theresa Kobe, Nathan Spreng, Melissa McSweeney, Nathalie Nilsson, Morteza Pishnamazi, Christophe Bedetti, Louise Hudon, Claudia Greco, Marianne Chapleau, Frederic St-Onge, Sophie Boutin, Maiya Geddes, Simon Ducharme, Gabriel Jean, Elisabeth Sylvain, Marie-Josee Ã‰lie, Gloria Leblond-Baccichet, Jean-Paul Soucy, Hazal Ozlen, Julie Bailly, Bery Mohammediyan, Yalin Chen, Jordana Remz, Michael W Weiner, Ronald Peterson, Clifford R. Jack, William Jagust, John Q Trojanowki, Arthur W Toga, Laurel Beckett, Robert C Green, Andrew J Saykin, John C Morris, Richard J Perrin, Leslie M Shaw, Maria Carrillo, William Porter, Lisa Barnes, Marie Bernard, Hector Gonzalez, Carole Ho, John K Hsiao, Jonathan Jackson, Eliezer Masliah, Donna Masterman, Ozioma Okonkwo, Laurie Ryan, Nina Silverberg, Adam Fleisher, Diana Truran Sacrey, Juliet Fockler, Cat Conti, Dallas Veitch, John Neuhaus, Chengshi Jin, Rachel Nosheny, Miriam Ashford, Derek Flenniken, Adrieene Kormos, Tom Montine, Micheal Rafii, Rema Raman, Gustavo Jimenez, Micheael Donohue, Devon Gessert, Jennifer Salazar, Caileigh Zimmerman, Yuliana Cabrera, Sarah Walter, Garrett Miller, Godfrey Coker, Taylor Clanton, Lindsey Hergesheimer, Stephanie Smith, Olusegun Adegoke, Payam Mahboubi, Shelley Moore, Jeremy Pizzola, Elizabeth Shaffer, Danielle Harvey, Arivn Forghanian-Arani, Bret Borowski, Chad Ward, Christopher Schwarz, David Jones, Jeff Gunter, Kejal Kantarci, Matthew Senjen, Prashanthi Vermuri, Robert C Reid, Nick C Fox, Ian Malone, Paul Thompson, Sophia I Tohomopoulous, Talia M. Nir, Neda Jahanshad, Charles DeCarli, Alexander Knaack, Evan Fletcher, Duygu Tosun-Turgut, Stephanie Rossi Chen, Mark Choe, Karen Crawford, Paul A. Yushkevich, Sandhitsu Das, Robert A. Koeppe, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, John C. Morris, Richard Perrin, Nigel J. Cairns, Erin Householder, Erin Franklin, Haley Bernhardt, Lisa Taylor-Reinwald, Magdalena Korecka, Michal Figurski, Scott Neu, Kwangski Nho, Shannon Risacher, Liana G Apostolova, Li Shen, Tatiana M Foroud, Kelly Nudelman, Kelley Faber, Kristi Wilmes, Leon Thal, Keith Johnson, Dorene Rentz, Rebecca E. Amariglio, Deborah Blacker, Rachel Buckley, Jasmeer P. Chhatwal, Brad Dickerson, Nancy Donovan, Michelle Farrell, Geoffroy Gagliardi, Jennifer Gatchel, Edmarie Guzman-Velez, Heidi Jacobs, Roos Jutten, Cristina Lois Gomez, Gad Marshall, Kate Oaoo, Enmanuelle Pardilla-Delgado, Julie Price, Prokopis Prokopiou, Yakeel Quiroz, Gretchen Reynolds, Aaron Schultz, Stephanie Schultz, Jorge Sepulcre, Irina Skylar-Scott, Patrizia Vannini, Clara Vila-Castelar, Hyun-Sik Yang
Journal: JAMA Neurology (2022)

Preventive trials of anti-amyloid agents might preferably recruit persons showing earliest biologically relevant β-amyloid (Aβ) binding on positron emission tomography (PET).To investigate the timing at which Aβ-PET binding starts showing associations with other markers of Alzheimer disease.This longitudinal multicentric cohort study included 3 independent cohorts: Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) (data collected from 2012-2020), Alzheimer Disease Neuroimaging Initiative (ADNI) (data collected from 2005-2019), and Harvard Aging Brain Study (HABS) (data collected from 2011-2019). In a 3-tiered categorization of Aβ-PET binding spatial extent, individuals were assigned as having widespread Aβ deposition if they showed positive signal throughout a designated set of brain regions prone to early Aβ accumulation. Those with binding in some but not all were categorized as having regional deposition, while those who failed to show any criterion Aβ signal were considered Aβ-negative. All participants who were cognitively unimpaired at their first Aβ PET scan.Differences in cerebrospinal fluid (CSF), genetics, tau-PET burden, and cognitive decline.A total of 817 participants were included, including 129 from the PREVENT-AD cohort (mean [SD] age, 63.5 [4.7] years; 33 [26%] male; 126 [98%] White), 400 from ADNI (mean [SD] age, 73.6 [5.8] years; 190 [47%] male; 10 [5%] Hispanic, 338 [91%] White), and 288 from HABS (mean [SD] age, 73.7 [6.2] years; 117 [40%] male; 234 [81%] White). Compared with Aβ-negative persons, those with regional Aβ binding showed proportionately more APOE ε4 carriers (18 [64%] vs 22 [27%] in PREVENT-AD and 34 [31%] vs 38 [19%] in ADNI), reduced CSF Aβ1-42 levels (F = 24 and 71), and greater longitudinal Aβ-PET accumulation (significant β = 0.019 to 0.056). Participants with widespread amyloid binding further exhibited notable cognitive decline (significant β = -0.014 to -0.08), greater CSF phosphorylated tau181 (F = 5 and 27), and tau-PET binding (all F &gt; 7.55). Using each cohort's specified dichotomous threshold for Aβ positivity or a visual read classification, most participants (56% to 100%, depending on classification method and cohort) with regional Aβ would have been classified Aβ-negative.Regional Aβ binding appears to be biologically relevant and participants at this stage remain relatively free from CSF phosphorylated tau181, tau-PET binding, and related cognitive decline, making them ideal targets for anti-amyloid agents. Most of these individuals would be classified as negative based on classical thresholds of Aβ positivity.